Abstract

Background Older women presenting with ST-segment elevation myocardial infarction (STEMI) are less likely to receive revascularization and have worse outcomes relative to their male counterparts.

Objectives This study sought to determine temporal trends and sex differences in revascularization and in-hospital outcomes of younger patients with STEMI.

Methods We used the 2004 to 2011 Nationwide Inpatient Sample databases to identify all patients age 18 to 59 years hospitalized with STEMI. Temporal trends and sex differences in revascularization strategies, in-hospital mortality, and length of stay were analyzed.

Results From 2004 to 2011, of 1,363,492 younger adults (age <60 years) with acute myocardial infarction, 632,930 (46.4%) had STEMI. Younger women with acute myocardial infarction were less likely than men to present with STEMI (adjusted odds ratio [OR]: 0.74; 95% confidence interval [CI]: 0.73 to 0.75). Younger women with STEMI were less likely to receive reperfusion as compared with younger men (percutaneous coronary intervention adjusted OR: 0.74; 95% CI: 0.73 to 0.75) (coronary artery bypass grafting adjusted OR: 0.61; 95% CI: 0.60 to 0.62) (thrombolysis adjusted OR: 0.80; 95% CI: 0.78 to 0.82). From 2004 to 2011, use of percutaneous coronary intervention for STEMI increased in both younger men (63.9% to 84.8%; ptrend < 0.001) and women (53.6% to 77.7%; ptrend < 0.001). In-hospital mortality was significantly higher in younger women compared with men (4.5% vs. 3.0%; adjusted OR: 1.11; 95% CI: 1.07 to 1.15). There was an increasing trend in risk-adjusted in-hospital mortality in both younger men and women during the study period. Length of stay decreased in both younger men and women (ptrend < 0.001).

Conclusions Younger women are less likely to receive revascularization for STEMI and have higher in-hospital mortality as compared with younger men. Use of percutaneous coronary intervention for STEMI and in-hospital mortality have increased, whereas length of stay has decreased in both sexes over the past several years.

Despite a significant decrease in death rates associated with cardiovascular diseases in the United States over the last decade, the burden remains high with 1 in every 3 deaths still attributed to cardiovascular disease (1). Acute myocardial infarction (AMI) continues to be a major cause of morbidity and mortality and affects a substantial proportion of the population (2–4). Recent data suggest that the hospitalization rates for AMI in younger patients have remained unchanged in the past decade (5). However, there is a paucity of data on the contemporary trends and sex differences in reperfusion and outcomes in younger patients with ST-segment elevation myocardial infarction (STEMI). In this study, we describe the temporal trends in reperfusion (thrombolysis, percutaneous coronary intervention [PCI], and coronary artery bypass grafting [CABG]) and in-hospital outcomes of STEMI in younger adults (18 to 59 years of age) in the United States. It has been previously reported that women are less likely than men to undergo revascularization or invasive procedures for AMI (6,7). Hence, we analyzed the sex-stratified trends in reperfusion to further study the temporal changes over the study period.

Methods

Data source

We analyzed data from the Nationwide Inpatient Sample (NIS) files from 2004 to 2011, which contains data on inpatient hospital stays from states (n = 46 in 2011) participating in the Healthcare Cost and Utilization Project. Each year the NIS provides data on roughly 8 million hospitalizations from about 1,000 hospitals. The NIS is designed to approximate a 20% sample of U.S. community hospitals, defined as “all non-federal, short-term, general, and other specialty hospitals, excluding hospital units of institutions,” representing more than 95% of the U.S. population. Criteria used for stratified sampling of hospitals into the NIS include ownership, bed size, teaching status, urban/rural location, and U.S. region. All discharges from sampled hospitals are included in the NIS database. The NIS is an all-payer database that covers all patients, including those covered by Medicare, Medicaid, or private insurance, and those who are uninsured. Inpatient stay records in the NIS include clinical and resource use information available from discharge abstracts derived from state-mandated hospital discharge reports. Discharge weights provided by the NIS allow extrapolation to calculate expected national hospitalization rates (8).

Study population

From 2004 to 2011, a total of 63,911,033 hospital records were included in the NIS, corresponding to a national estimate of 313,736,891 hospital discharges in the United States. We used the International Classification of Diseases-Ninth Edition-Clinical Modification (ICD-9-CM) codes 410.x1 to identify all patients 18 to 59 years of age with the principal diagnosis of AMI (n = 1,588,206). We chose the principal diagnosis because it is considered the primary reason for hospital admission. We excluded hospitalizations with missing data on patient age, sex, length of stay (LOS), or in-hospital death (n = 947). We also excluded discharges in which patients were admitted and discharged alive on the same day (n = 41,746). Lastly, we excluded discharges in which patients were hospitalized from other hospitals (n = 182,020) to avoid duplication of records, leaving a cohort of 1,363,492 patients with AMI. Patients with the principal diagnosis of STEMI were then identified using ICD-9-CM codes 410.11 to 410.61, 410.81, and 410.91 and comprised our final study cohort (n = 632,930 [46.4% of all AMI]). ICD-9-CM codes were also used to identify patients who underwent coronary angiography (88.55, 88.56, 37.22, 37.23), thrombolysis (99.10, V45.88), PCI (00.66, 36.01, 36.02, 36.05, 36.06, 37.07), or CABG (36.1x). Because primary PCI is the treatment of choice for STEMI, we also determined the proportion of patients who received PCI on the day of admission.

Outcomes measured

We initially studied the overall and age group–specific trends in proportion of STEMI in younger men and women with AMI. We then examined the trends in thrombolysis, PCI, and CABG in younger men and women with STEMI. Our primary outcome of interest was all-cause, in-hospital mortality, defined as “died” during the hospitalization encounter in the NIS database. The average LOS was used as a secondary outcome. We analyzed the overall and age group–specific trends in in-hospital mortality and LOS in younger men and women with STEMI. We also compared differences in proportion of STEMI, use of thrombolysis/PCI/CABG for STEMI, in-hospital mortality, and LOS among younger men and women.

Patient and hospital characteristics

Baseline patient characteristics included were demographics (age [stratified into subgroups of 18 to 29, 30 to 39, 40 to 49, and 50 to 59 years] and race/ethnicity), primary expected payer, weekday versus weekend admission, median household income for patient’s ZIP code, 29 Elixhauser comorbidities as defined by the Agency for Healthcare Research and Quality, and other clinically relevant comorbidities (smoking, dyslipidemia, known coronary artery disease, family history of coronary artery disease, prior MI, prior PCI, prior CABG, carotid artery disease, and atrial fibrillation). A list of ICD-9-CM and Clinical Classifications Software codes used to identify comorbidities is provided in the Online Table 1. We also included hospital-level variables, such as teaching status, bed size (small, medium, and large), hospital region (Northeast, Midwest, South, and West), and location (rural or urban).

Statistical analysis

Weighted data were used for all statistical analyses. For trend analysis, we used the Cochrane-Armitage test for categorical variables and linear regression for continuous variables. For descriptive analyses, patient demographics, comorbidities, hospital characteristics, in-hospital procedures/treatments, and in-hospital outcomes were compared among men and women using Pearson chi-square test for categorical variables and Student t test for continuous variables.

To determine the associations of sex with treatment choice and outcomes (in-hospital mortality, LOS), multivariable logistic or linear regression models were constructed using generalized estimating equations with exchangeable working correlation matrix. This was done to account for clustering of outcomes within hospitals. Variables included in the regression model were age, primary expected payer, weekday versus weekend admission, 29 Elixhauser comorbidities, other clinically relevant comorbidities (smoking, dyslipidemia, known coronary artery disease, family history of coronary artery disease, prior MI, prior PCI, prior CABG, carotid artery disease, and atrial fibrillation), and hospital characteristics (region, bed size, location, and teaching status). Race/ethnicity was missing in 23.6% of the study population and was therefore not included in the model. For in-hospital mortality, after adjusting for the previously mentioned covariates, we further adjusted for PCI (on Day 0) to determine if differences in treatment can explain the difference in mortality between men and women. Risk-adjusted mortality per year was calculated as described previously (9). For trend analyses, we included the independent variable “year” as a continuous variable in the regression model to obtain unadjusted and adjusted odds ratio (OR) per year. This approach has been used in previous studies (10). For LOS we used multivariable linear regression analysis adjusting for all the previously mentioned variables. Because LOS had a positively skewed distribution, we used log transformation of LOS as the dependent variable.

Statistical analysis was performed using IBM SPSS Statistics 20.0 (IBM Corp., Armonk, New York). All p values were 2-sided with a significance threshold of p < 0.05. Categorical variables are expressed as percentage and continuous variables as mean ± SD. OR and 95% confidence interval (CI) are used to report the results of logistic regression.

There was an increasing trend in smoking, dyslipidemia, coronary artery disease, prior MI, prior PCI, diabetes mellitus, hypertension, obesity, peripheral vascular disease, and chronic renal failure in both younger men and women over the study period (Online Tables 2 and 3).

Trends in proportion of STEMI

In the overall AMI population, younger women were less likely than men to present with a STEMI (38.4% vs. 49.4%, p < 0.001; adjusted OR: 0.74; 95% CI: 0.73 to 0.75; p < 0.001). The proportion of STEMI decreased in both younger men and women during the study period (54.0% in 2004 to 45.2% in 2011 in men, and 44.6% in 2004 to 34.7% in 2011 in women, ptrend < 0.001). Although there was a decrease in the absolute number of STEMIs from 2004 to 2011 in younger men (61,304 to 58,299; ptrend = 0.004) and women (18,354 to 17,330; ptrend < 0.001), the decrease in proportion of STEMI was mainly caused by a substantial increase in the absolute number of non-ST-segment elevation myocardial infarctions (NSTEMIs) over the study period (younger men, 52,265 to 70,737; ptrend < 0.001; younger women, 22,827 to 32,589; ptrend < 0.001). Similar findings were observed across all age-stratified subgroups (Table 2).

There was an increasing trend in use of PCI for STEMI in both younger men and women during the study period (from 63.9% in 2004 to 84.8% in 2011 in men, and 53.6% in 2004 to 77.7% in 2011 in women; ptrend < 0.001) (Figure 2, Table 3). Similar trends were observed in the use of PCI on Day 0 in both groups (41.9% in 2004 to 71.2% in 2011 in men, and 33.0% in 2004 to 63.0% in 2011 in women; ptrend < 0.001). Use of CABG decreased in both groups (9.2% in 2004 to 6.3% in 2011 in men, and 7.0% in 2004 to 5.8% in 2011 in women; ptrend < 0.001) (Figure 2, Table 3).

PCI use with increasing number of comorbidities

To study the influence of baseline, coded comorbidities on PCI use rates, we divided younger men and women into 4 groups on the basis of the number of Elixhauser comorbidities (0, 1, 2, and 3+). Younger women were less likely to receive revascularization in all groups, and the revascularization disparity between younger men and women was greatest in patients with zero comorbidities (9.3%) and least in patients with 3+ comorbidities (3.3%). The interaction between sex and number of comorbidities was significant in the multivariable model (p interaction <0.001) (Figure 3).

Differences in use of PCI for STEMI between younger men and women with increasing number of Elixhauser comorbidities. p < 0.001 for men versus women for all categories. Abbreviations as in Figures 1 and 2.

Women had longer average LOS than men in the overall study population (4.35 vs. 4.00 days; unadjusted parameter estimate, 1.05; 95% CI: 1.04 to 1.05; adjusted parameter estimate, 1.04; 95% CI: 1.03 to 1.06; p < 0.001). Average LOS decreased in both men and women over the study period (4.13 days in 2004 to 3.86 days in 2011 in men, and 4.59 days in 2004 to 4.24 days in 2011 in women; ptrend < 0.001) (Figure 4B, Online Table 5).

Discussion

In this large, multi-institutional, population-based observational study of younger adults in the United States, we observed that among patients with AMI, women were less likely than men to present with STEMI. There was a temporal decline in the proportion of STEMI in both sexes as a result of a small decrease in the absolute number of STEMIs, but mainly because of a substantial increase in the absolute number of NSTEMIs. Although there was an increase in use of PCI in both younger men and women with STEMI, women were less likely than men to undergo PCI. Younger women with STEMI had higher in-hospital mortality and longer average LOS than younger men. There was a temporal increase in risk-adjusted in-hospital mortality and decrease in LOS in both younger men and women (Central Illustration).

Using data from the NIS databases from 2001 to 2010, Gupta et al. (5) recently reported that hospitalization rates for AMI (both STEMI and NSTEMI) have remained unchanged over the last decade in younger adults age 30 to 54 years in the United States. However, this study did not explore the differential trends in STEMI and NSTEMI in younger adults or trends and sex differences in reperfusion strategies. Our current findings of decline in the proportion of STEMI in younger men and women, coupled with the observations of Gupta et al. (5), suggest that the proportion (and absolute number) of NSTEMI has increased in recent years in younger U.S. adults, perhaps caused in part by more widespread use of sensitive cardiac biomarker assays resulting in more cases of unstable angina being classified as NSTEMI (11). Nonetheless, we did observe a small decline in the absolute number of STEMIs in both younger men and women over the study period. Furthermore, in the current study, we also examined temporal trends and sex differences in revascularization for STEMI in younger adults. Our analysis showed that although there have been temporal increases in revascularization rates for STEMI both in younger men and women, there are persistent sex-based differences in the use of revascularization therapies and associated in-hospital outcomes among younger adults with STEMI.

Our findings of lower STEMI rates in younger women as compared with men parallel those of previous studies (12,13). Rates of STEMI in the general population have declined over the last several years, as shown in numerous recent studies (4,14,15). Our current study extends these findings to younger adults between 18 and 59 years of age.

We observed that younger women with STEMI were less likely to receive revascularization than younger men. We also found that whereas the use of thrombolysis and PCI increased over the years in both men and women, the use of CABG decreased. Previous reports on the overall STEMI population have also described similar findings (7,16,17). Results from the recent prospective U.S. VIRGO (Variations in Recovery: Role of Gender on Outcomes of Young AMI Patients) study showed that in young patients age 18 to 55 years with STEMI who were eligible for reperfusion, women were more likely to be untreated than men (18).

A novel finding from our current study is the narrowing of absolute differences in the use of PCI for STEMI between younger men and women with increasing number of baseline comorbidities (Figure 3). Despite narrowing of the absolute differences, younger women were still less likely to receive PCI for STEMI. Several reasons can be postulated to explain these findings. Younger women with AMI are less likely to have chest pain/discomfort and are more likely to have atypical presentations (12,19). It is plausible that this may lead to more delayed presentation and underrecognition of STEMI at initial medical contact, thus precluding acute reperfusion for STEMI. Lower revascularization rates can also be explained, in part, because of higher frequency of alternative etiologies, such as Takotsubo (stress) cardiomyopathy, spontaneous coronary artery dissection, and coronary vasospasm in younger women. Another potential reason for lower use of revascularization in women could be the almost 2-fold increased risk of bleeding as compared with men (20,21). This potentially higher bleeding risk can prevent women with atypical symptoms from getting guideline-specific interventional therapies.

Excess early mortality after AMI in younger women was first described by Vaccarino et al. (22). They reported that the younger the age, the greater the risk of in-hospital mortality among women as compared with men. Concordant with findings of previous studies in the overall STEMI population (12,17,23), we observed that younger women with STEMI had higher risk-adjusted in-hospital mortality as compared with younger men. In our study, the difference in mean age at presentation between women and men was very small. We did observe a higher prevalence of comorbidities in younger women as compared with men. In addition to lower use of revascularization, another likely reason for higher in-hospital mortality in younger women in STEMI could be the lower use of adjunctive medical therapies as shown in previous studies in the overall STEMI population (24–26). Women with STEMI also experience treatment delays post-hospital arrival with significantly longer door-to-electrocardiography, door-to-needle, and door-to-balloon times (7,17,25). Of note, men are also more likely than women to die before arrival to hospital and this may possibly confound the excess in-hospital mortality observed in women (26). Using data from GWTG-CAD, Bangalore et al. (27) previously reported that compared with men in the corresponding age category, both younger and older women with STEMI are less likely to receive guideline-recommended medical therapy both at admission and at hospital discharge. Interestingly, there was a significant interaction between age and sex such that sex differences in STEMI performance measures were greater in the younger cohort than the older cohort. Data from the VIRGO study also showed that young women with STEMI were more likely to exceed in-hospital and transfer-time guidelines for PCI than men and more likely to exceed door-to-needle times. After multivariate adjustment, sex was found to be an independent factor in exceeding reperfusion guidelines (18). Additional pathophysiological differences could contribute to the higher mortality in younger women with STEMI. Younger women have less extensive coronary artery disease and they have lesser myocardial ischemic preconditioning, resulting in a greater vulnerability to acute ischemia (28). Contrary to the declining mortality rates in the overall STEMI population (14,16,29), there was a significant temporal increase in risk-adjusted in-hospital mortality in younger men and women with STEMI. In contrast, Gupta et al. (5) recently reported a decline in observed in-hospital mortality in younger women but not in men with AMI (STEMI and NSTEMI). Patients with NSTEMI represent a lower-risk population and were not included in our current study. Furthermore, we found an increasing trend in “risk-adjusted” mortality. Possible explanations for these adverse trends may include increasing comorbidities, atypical symptoms, delayed presentation, and unmeasured covariates. However, further studies are needed to confirm our findings and determine the factors responsible for the increasing trends in risk-adjusted mortality in younger adults with STEMI.

Study limitations

Our data included only hospitalized patients with STEMI and did not account for out-of-hospital deaths. Additionally, we could assess only in-hospital outcomes and could not determine whether post-discharge mortality was different between younger men and women to offset the sex difference noted in in-hospital mortality. Patients in the NIS database are not linked, and as a result we were not able to differentiate initial STEMIs from subsequent STEMIs. Given the lack of angiographic data, we were not able to account for extent and severity of coronary artery disease, and the reason why revascularization strategies were not used in individual patients could not be ascertained. There was no information available on important STEMI performance measures, such as door-to-electrocardiography, door-to-needle, and door-to-balloon times. Given the abstracted nature of the database, we relied on administrative data to obtain information on comorbidities. Accuracy of certain variables may be related to hospital coding practices and the observed temporal increase in comorbidities may be related to incentive-driven diagnosis-related group upcoding. There were no data available on the use of guideline-recommended adjunctive medical therapies. Finally, residual measured or unmeasured confounding could have accounted for some of our findings.

Conclusions

Among younger adults with AMI, women were less likely to present with STEMI as compared with men. There was a decline in proportion of STEMI in both younger men and women over the study period. Younger women with STEMI were less likely to receive revascularization and had higher unadjusted and risk-adjusted in-hospital mortality as compared with men. There was a temporal increase in the use of revascularization in younger adults with STEMI. Risk-adjusted in-hospital mortality increased, whereas LOS decreased over the study period in both younger men and women with STEMI. These data present a persisting opportunity to improve national STEMI care processes and outcomes, and to bridge the sex-disparity in providing care to younger patients with STEMI.

Perspectives

COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Young men hospitalized with STEMI are more likely to survive than young women with this condition.

COMPETENCY IN SYSTEMS-BASED PRACTICE: Despite increased guideline-directed use of percutaneous coronary intervention for patients with STEMI, young women are less likely than young men to undergo timely revascularization.

TRANSLATIONAL OUTLOOK: Prospective studies are needed to explore the factors responsible for sex-related disparities in revascularization and outcomes in patients with STEMI and evaluate strategies to address them.

Appendix

Appendix

For supplemental tables, please see the online version of this article.

Footnotes

Dr. Fonarow has consulted with AstraZeneca, Bayer, Janssen, and Novartis. Dr. Bhatt is on the advisory board of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; is on the board of directors of Boston VA Research Institute and Society of Cardiovascular Patient Care; is the chair of the American Heart Association Get With The Guidelines Steering Committee; is on the Data Monitoring Committees of Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, and Population Health Research Institute; has received honoraria from the American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org), Belvoir Publications (editor in chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor; associate editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (chief medical editor, Cardiology Today’s Intervention), and WebMD (CME steering committees); is a deputy editor of Clinical Cardiology; has received research funding from Amarin, AstraZeneca, Biotronik, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi, and The Medicines Company; is site coinvestigator for Biotronik and St. Jude Medical; is a trustee for the American College of Cardiology; and has performed unfunded research with FlowCo, PLx Pharma, and Takeda. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. A part of this study was presented at the American College of Cardiology 64th Annual Scientific Sessions 2015 in San Diego, California. Drs. Khera and Kolte contributed equally to this work.

(2008) Trends in presenting characteristics and hospital mortality among patients with ST elevation and non-ST elevation myocardial infarction in the National Registry of Myocardial Infarction from 1990 to 2006. Am Heart J156:1026–1034.

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